Submissions for variant NM_000251.3(MSH2):c.366+1G>T

dbSNP: rs267607924

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076573	SCV000107605	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759832	SCV000889436	pathogenic	not provided	2017-10-16	criteria provided, single submitter	clinical testing
Invitae	RCV001059850	SCV001224500	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 16395668; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 91071). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch Syndrome (PMID: 16395668, 31615790; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV002453390	SCV002615667	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-05-17	criteria provided, single submitter	clinical testing	The c.366+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 2 of the MSH2 gene. This alteration has been reported in one patient diagnosed with HNPCC (Hereditary Non Polyposis Colorectal Cancer); however, the patient's clinical and family history information was not provided (Sjursen W et al. Mol Genet Genomic Med. 2016 Jan 11;4(2):223-31). In one functional study, RNA studies have suggested that this alteration leads to the skipping of exon 2 in the MSH2 gene (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003452936	SCV004186727	likely pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.